Attenuation of Tumor Development in Mammary Carcinoma Rats by Theacrine, an Antagonist of Adenosine 2A Receptor

• Published in: Molecules Vol. 26; no. 24; p. 7455
• Main Authors: Jhuo, Cian-Fen, Hsu, Yu-Yu, Chen, Wen-Ying, Tzen, Jason T. C.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.12.2021; MDPI
• Subjects: Adenosine; adenosine 2A receptor; adenosine 2A receptor; anti-tumor immunity; mammary carcinoma; theacrine; Adenosine A2 Receptor Antagonists; Adenosine A2 Receptor Antagonists - pharmacology; Animals; anti-tumor immunity; Apoptosis; Breast cancer; Caffeine; Cancer therapies; Drug dosages; Female; Humans; Hydrogen bonds; Immunotherapy; Kinases; mammary carcinoma; Mammary Neoplasms, Experimental; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; MCF-7 Cells; Neoplasm Proteins; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Organic chemistry; Physiology; QD241-441; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptor, Adenosine A2A - metabolism; theacrine; Tumors; Uric Acid; Uric Acid - analogs & derivatives; Uric Acid - pharmacology; theacrine; adenosine 2A receptor; anti-tumor immunity; mammary carcinoma
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26247455

Caffeine has been reported to induce anti-tumor immunity for attenuating breast cancer by blocking the adenosine 2A receptor. Molecular modeling showed that theacrine, a purine alkaloid structurally similar to caffeine, might be an antagonist of the adenosine 2A receptor equivalent to or more effective than caffeine. Theacrine was further demonstrated to be an effective antagonist of the adenosine 2A receptor as its concurrent supplementation significantly reduced the elevation of AMPK phosphorylation level in MCF-7 human breast cells induced by CGS21680, an agonist of adenosine 2A receptors. In an animal model, the development of mammary carcinoma induced by 7,12-Dimethylbenz[a]anthracene in Sprague–Dawley rats could be attenuated by daily supplement of theacrine of 50 or 100 mg/kg body weight. Both expression levels of cleaved-caspase-3/pro-caspase-3 and granzyme B in tumor tissues were significantly elevated when theacrine was supplemented, indicating the induction of programmed cell death in tumor cells might be involved in the attenuation of mammary carcinoma. Similar to the caffeine, significant elevation of interferon-γ and tumor necrosis factor-α was observed in the serum and tumor tissues of rats after the theacrine supplement of 50 mg/kg body weight. Taken together, theacrine is an effective antagonist of adenosine 2A receptors and possesses great potential to be used to attenuate breast cancer.